Although tobacco smoke and alcohol account for most cases of oral cancer, few smokers and drinkers eventually acquire this disease. The main goal of this study is to determine whether differences in constitutive function of certain biotransformation enzymes (which metabolize tobacco smoke and alcohol) modify risk for oral cancer among smokers and drinkers, and thereby account for some of the observed differences in susceptibility. To meet this goal, we will conduct a case-control study of oral cancer in the Pittsburgh area. Cases (N=244) will be men and women identified through the Ear, Nose, and Throat, and Oncology Offices at UPMC with squamous cell carcinoma of the oral cavity newly diagnosed between 01/01/99 and 12/31/02, who are 18-74 years of age, and reside in one of 16 counties in the Tri-State area (including western Pennsylvania, eastern Ohio and northeastern Western Virginia). Neighborhood controls (N=488) will be men and women identified through Voters' Registration lists (for Allegheny County in Pennsylvania) or Motor Vehicle Drivers' License lists (for all other counties) who are without oral cancer and match the cases on age, gender, race and zip code. Two controls will be matched to each case. Eligible cases and controls will have a history of cigarette use (at least 10 pack-years) or alcohol use (at least 1 alcoholic beverage per week). In person interviews will cover demographic variables, detailed history of tobacco and alcohol use, diet, ethnic background and family history of cancer. Blood will be drawn, and DNA extracted and analyzed for genetic variants of the following polymorphic biotransformation enzymes: CYP1A1, CYP2E1, GSTM1, GSTT1, GSTP1, mEH, MPO, NAT2, ALDH2, ADH2 and ADH3. Each of these enzymes is important in the metabolism of either alcohol or tobacco smoke, or both. We will measure relationships between each genetic enzyme variant and risk for oral cancer, as well as the joint effects of these polymorphisms on risk. We will also examine exposures, e.g. diet, that may modify or confound these relationships. Identification of genetic biomarkers for susceptibility to oral cancer could be used to focus screening and intervention efforts on individuals who at highest risk for this disease.